Brain aging is a significant health issue and a risk factor for Alzheimer?s disease (AD). Our published results showed that elderly mice had worse learning and memory than younger mice. Similar finding occurred in rats. We have also shown that carboxyl-terminal modulator protein (CTMP), an endogenous negative regulator of the pro-survival protein Akt, increased with aging and this increase may contribute to the decreased brain ischemic tolerance in rats. Our preliminary studies showed that autophagy was decreased with aging and that CTMP silencing increased autophagy in the brain of elderly rats. Decreased autophagy is considered a process of brain aging. Our preliminary study also showed that amyloid ? peptide (A?) increased CTMP and that neutralizing A? attenuated CTMP increase in aging brain. A? is increased with aging and A? accumulation in the brain is considered a feature of AD. In addition, presumed CTMP promoter regions had binding sites for Zic2, Zic2 bound CTMP promoter regions and Zic2 was decreased with aging in our preliminary study. Thus, we hypothesize that aging-related CTMP increase participates in the aging-related cognitive decline via deceasing autophagy and that the aging-related CTMP increase may be regulated by Zic2, which is modulated by A?. In this project, we will test these hypotheses by using different ages of Fischer 344 rats. CTMP will be silenced in the brain of these rats. Their autophagy in the brain, learning and memory will be tested. The regulation of CTMP expression, especially the role of A? in regulating CTMP expression with aging will be determined by molecular technology under in vitro and in vivo conditions. These studies may not only improve our understanding of brain aging but also define a novel mechanism for A? to induce detrimental effects. Thus, these studies may identify potential targets for attenuating brain aging processes and reducing risks for AD.